Olfactory function is affected early in Alzheimer's disease. Odor identification is impaired at early stages of the disease, and the ability to detect odors appears to be increasingly impaired as the disease progresses. At the anatomical level, postmortem studies indicate that the regions of the brain most severely affected in Alzheimer's disease include important elements of the olfactory system. Thus, neurofibrillary tangles and neuritic plaques, classical markers of Alzheimer's disease occur in the olfactory bulb, the anterior olfactory nucleus and the prepiriform cortex. In addition, although the data are not equivocal, the olfactory neuroepithelium of Alzheimer's patients displays ultrastructural abnormalities, crystalline deposits and extensive neurite accumulations that stain strongly for antibodies that recognize phosphorylated forms of the microtubule-associated protein tau, a protein enriched in neurofibrillary tangles and neuritic plaques from Alzheimer's patients. Preliminary studies of ion regulation from the laboratories of Diego Restrepo (Sponsor)and Nancy Rawson (Collaborator) indicate that olfactory receptor neurons (ORNs) from Alzheimer's disease patients have altered regulation of intracellular calcium. In addition, studies from the laboratory of Bruce Jafek at UCHSC (Co-Sponsor) indicate that there are changes in mitochondrial volume in olfactory support cells. The purpose of this project is to elucidate functional changes in the olfactory epithelium secondary to Alzheimer's disease. In turn, the results should provide insight into the etiology of Alzheimer's disease and in particular may have diagnostic and therapeutic significance for this disease. A multidisciplinary approach involving cell biology, biophysics and psychophysics will be undertaken towards these goals. The specific aims of this proposal are delineated as follows: Aim I. Determine whether intracellular calcium regulation is impaired in olfactory neurons from Alzheimer's disease patients. Aim II. Study electrical membrane properties and signal transduction in normal and Alzheimer's disease patients. Aim III. Study changes in ion homeostasis in olfactory mucous in Alzheimer's disease patients.